Summary Psychological stress and hypothalamic-pituitary-adrenal (HPA) axis dysfunction play a role in many disorders including Alzheimer?s disease (AD), major depression, metabolic syndrome, and sarcopenia. Chronic high levels of stress and elevated corticosteroids are also hypothesized to act as ?accelerants? of many age-associated diseases and phenotypes. Further, numerous studies report an association between increased stress and HPA axis dysfunction with increased rates of cognitive decline and hippocampal and brain atrophy in late-life dementia. Our interest in the HPA axis stemmed from rodent model data implicating psychological stress, corticotropin-releasing hormone/factor (CRH/CRF), and corticosterone, as factors that impact amyloid and tau pathology and age-associated declines in cognitive function. Indeed, suppression of the HPA axis theoretically represents a unique therapeutic strategy in AD, as it has been implicated in regulating the underlying A? and tau proteinopathies and independently affecting, presumably through corticosteroid excess, brain atrophy and cognitive decline. Unfortunately, testing the role of HPA axis in AD and cognitive aging, has been hindered by the lack of small molecule therapeutics that effectively suppress HPA axis activation in humans. As an alternative to small molecule approaches, we have successfully developed a picomolar affinity IgG1 monoclonal antibody (mAb) targeting CRF (anti-CRF mAb, CTRND05) that dose-dependently blocks stress-induced increases in corticosterone, and can rapidly reverse select Cushingoid phenotypes in mice overexpressing CRF. Metabolic and immunologic studies reveal numerous effects consistent with long-lasting suppression of the HPA-axis; multi-organ transcriptomic studies shows robust regulation of numerous genes that may mediate the physiologic effects of CTRND05. We hypothesize that passive immunotherapy targeting CRF represents a novel, translatable, therapeutic approach to AD and possibly many other disorders. Through pleiotropic actions, anti-CRF immunotherapy may slow the development of A? and tau pathologies as well as brain atrophy and cognitive decline. In this proposal, we will systematically and rigorously evaluate the therapeutic potential of this anti-CRF immunotherapy in appropriate preclinical models and develop companion theragnostic biomarkers. As CRF is completely conserved between humans and mice, and is present at similar concentrations, positive results from these studies will provide the rationale for testing of a humanized high affinity anti- CRF mAb for therapeutic benefit in humans.